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Cytochrome P 450 isoforms involved in melatonin metabolism in human liver microsomes
Abstract
Objective The present study was carried out to identify the cytochrome P450 enzyme(s) involved in the 6-hydroxylation and O-demethylation of melatonin.Methods The formation kinetics of 6-hydroxymelatonin and N-acetylserotonin were determined using human liver microsomes and cDNA yeast-expressed human enzymes (CYP1A2, 2C9 and 2C19) over the substrate concentration range 1-1000 microM. Selective inhibitors and substrates of various cytochrome P450 enzymes were also employed.Results Fluvoxamine was a potent inhibitor of 6-hydroxymelatonin formation, giving 50 +/- 5% and 69 +/- 9% inhibition at concentrations of 1 microM and 10 microM, respectively, after incubation with 50 microM melatonin. Furafylline, sulphaphenazole and omeprazole used at low and high concentrations substantially inhibited both metabolic pathways. cDNA yeast-expressed CYP1A2, CYP2C9 and CYP2C19 catalysed the formation of the two metabolites, confirming the data obtained with specific inhibitors and substrates.Conclusions Our results strongly suggest that 6-hydroxylation, the main metabolic pathway of melatonin, is mediated mainly, but not exclusively, by CYP1A2, the high-affinity enzyme involved in melatonin metabolism, confirming the observation that a single oral dose of fluvoxamine increases nocturnal serum melatonin levels in healthy subjects. Furthermore, the results indicate that there is a potential for interaction with drugs metabolised by CYP1A2 both at physiological levels and after oral administration of melatonin, while CYP2C19 and CYP2C9 are assumed to be less important.
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“Earlier research has identified that the majority of melatonin is metabolized through cytochrome (CYP) 1A2 [292,301], with lesser metabolic activity through CYP1A1, CYP1B1, and CYP2C19 [292,302].”
From Is Melatonin the “Next Vitamin D”?: A Review of Emerging Science, Clinical Uses, Safety, and Dietary Supplements (2022) · cites this paper as [301]
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Ursing, C., von Bahr, C., & Brismar, K. (2005)
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Metadata
- Authors
- Facciolá, G., Hidestrand, M., von Bahr, C., & Tybring, G.
- Affiliations
- Karolinska Institutet (SE)
- Venue
- European Journal of Clinical Pharmacology
- Published
- 2001-02-01
- Volume
- 56
- Issue
- 12
- Pages
- 881-888
- ISSN
- 0031-6970 (ISSN-L)
- 1432-1041
- OpenAlex
- W2025502084
- Semantic Scholar
- 75bffaa408d11f2d1001468f2f48f70361763b15
- Cited by
- 126
- References
- 0
- Citations by year
- 2026: 3 · 2024: 2 · 2023: 4 · 2022: 7 · 2021: 7 · 2020: 5 · 2019: 2 · 2018: 5 · 2017: 3 · 2016: 3 · 2015: 7 · 2014: 7 · 2013: 5 · 2012: 8
- FWCI
- 4.04
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- European Journal of Clinical Pharmacology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Eicosanoids and Hypertension Pharmacology
- Keywords
- melatonin metabolism, cytochrome P450, 6-hydroxymelatonin, N-acetylserotonin, CYP1A2, CYP2C9, CYP2C19, human liver microsomes, fluvoxamine, drug interactions, enzyme inhibition, furafylline, omeprazole
- MeSH terms
- Cells, Cultured, Chromatography, High Pressure Liquid, Cytochrome P-450 Enzyme System, Humans, Hydroxylation, Isoenzymes, Melatonin, Microsomes, Liver, Substrate Specificity, Fluvoxamine, Selective Serotonin Reuptake Inhibitors
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